The Foundations of Developmental Biology
Genetic Regulation of Development
Organizing the Multicellular Embryo
Dynamic Development at a Glance
The Developmental Biology Journal Club
OK, so symmetry isn't perfect.
At first glance, the left and right sides of our bodies are identical to one-another. However, internally, some of our visceral organs are displaced to one side. The heart, for example, loops to the right side. This looping is consistent in the vertebrates and occurs very early in development. Rare individuals have the opposite symmetry, which is known as situs inversus.
How is left-right asymmetry (often referred to as handedness) established during development? One way to begin studying this problem is to search for genes that are expressed early in development only on one side of the embryo and to formulate hypotheses on the origin and manifestation of handedness. Then experiments can be conducted to test these hypotheses.
In fact, a number of asymmetrically-expressed genes have been discovered, and we are on our way toward understanding how handedness develops. The first gene that was discovered to have asymmetrical expression is Sonic hedgehog, which is expressed on the left side of the gastrulating chick embryo. A screen of the expression patterns of developmentally significant genes in early chick embryos has revealed asymmetric patterns of mRNA expression for transcripts encoding a number of important signaling molecules (Table. 1, Fig. 1).
The demonstration of asymmetrical patterns of expression of these genes has made it possible to investigate the relationships among them so that regulatory interactions among them could be determined. The approaches used have included misexpression of the earlier-expressed genes on the opposite side to determine whether the expression of the later genes would change. In this way, a hierarchical pathway has been established (Fig. 2).
Initially, Shh is expressed throughout Hensen's node. (Hensen's node is a thickening at the anterior end of the primitive streak where presumptive notochord cells accumulate. It is functionally equivalent to the dorsal lip of the blastopore in amphibian embryos.) Somewhat later, activin -ßB is expressed on the right side of Hensen's node. As a consequence, cAct-RIIa is induced on the right side, shutting off expression of Shh on that side. As a consequence, Shh expression becomes limited to the left side of the node and in the notochord. These relationships were established by implanting activin-coated beads in the left side, which induced expression of cAct-RIIa and shut off expression of Shh. Likewise, applying beads coated with the activin inhibitor follistatin on the right side resulted in bilateral Shh expression, suggesting that the Shh asymmetry results from activin activity (Levin, 1997).
Asymmetric Shh expression induces a small domain of cells adjacent to the left side of the node to express nodal. A larger domain of nodal expression follows in the left lateral plate mesoderm. The role of Shh in inducing nodal expression was shown by applying ectopic Shh to the right side, which induces nodal in the right lateral plate mesoderm. Also, endogenous left-side Shh was removed by applying activin to the left side, which suppressed nodal expression (Levin, 1997).
What effects do the misexpression of these genes have on morphology? Misexpression of activin (which eliminates nodal expression), or Shh (which bilateralizes nodal expression) randomize heart looping (Levin et al., 1995). The cardiac precursor cells are in direct contact with the territory of nodal expression. Hence, it is possible that the asymmetric nodal signal causes the cardiac primordia on one side to initiate heart looping. This possibility is supported by the observation that administration of nodal can cause either a reversal of heart looping or symmetric hearts (Levin, 1997).
Figure 1. Genes with left-right asymmetric expression patterns in the chick. (A), cNot is symmetrically expressed around Hensen's node. (B), cAct-RIIa is expressed in the right side of the node. (C), Shh is expressed in the left side of Hensen's node. (D), HNF3-ß is expressed throughout the whole node but has a tail of expression in the left primitive ridge. (E) nodal is expressed in two domains, in the endoderm next to the left side of the node (red arrow), and the left lateral plate mesoderm. cWnt-8C (F), and PTC (G) are also asymmetrically expressed in the gastrulating chick embryo. White arrows, no expression; black arrows, expression domain. (From Levin, 1997. Reproduced from BioEssays with permission of The Company of Biologists.)
Figure 2. A LR pathway. (A), Diagram of asymmetrically expressed genes in a gastrulating chick embryo. (B), Diagram of the regulatory interactions between known members of the LR pathway. (From Levin, 1997. Reproduced from BioEssays with permission of The Company of Biologists.)
Lohr, J.L., Danos, M.C. and Yost, H.J. 1997. Left-right asymmetry of a nodal-related gene is regulated by dorsoanterior midline structures during Xenopus development. Development 124: 1465-1472.
T. Boettger, L. Wittler, M. Kessel. 1999. Curr. Biol. 9:271.
Links to Related Material
Left-right Asymmetry in Vertebrates: Report by Isaac et al. and Science Perspective by Robertson.
Levin, M. 1997. Left-right asymmetry in vertebrate embryogenesis. BioEssays 19: 287-296.
Levin, M., Johnson, R., Stern, C., Kuehn, M. and Tabin, C. 1995. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82: 1-20.
Riddle, R.D., Johnson, R.L., Laufer, E. and Tabin, C. 1993. Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75: 1401-1416.
Dynamic Development at a
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Leon Browder & Laurie Iten (Ed.) Dynamic Development
Last revised Thursday, June 25, 1998